Sexual transmission of HIV-1 involves complex processes involving exposure of the female genital tract to virus or infected cells and their transport to other sites, including local lymph nodes, where the virus replicates and establishes infection. It has been shown that Langerhans cells (LC) and dendritic cells (DC) capture the virus either from the vaginal surface or from top epithelium layers and transport it to draining and local lymph nodes, where it infects CD4+ T-cells. Intense development of topical microbicides is underway with the ultimate goal of decreasing the sexual transmission of HIV-1. Current efforts have been directed to inactivating the virus either at the surface of the vagina before entry, or in the squamous or stroma layers of the vaginal epithelium. Our physical transport modeling predicts that molecular drugs delivered as topical gels cannot reach draining or local lymph nodes. One possible way to deliver drugs to lymphoid sites surrounding the vagina is to use drug-loaded nanoparticles. Our preliminary results provide evidence indicating that nanoparticles can be delivered to local lymph nodes via vaginal application in a mouse model. To further develop this platform for use as a microbicide or prophylactic strategy, we propose the following plans for the R21/R33 application. In the R21 phase, we will study the delivery of quantum dots having different surface chemistry, including conjugation with targeting molecules, to determine the mode of their transport to different lymphoid sites. In the R33 phase, we will use drug-loaded nanoparticles and verify the applicability of this platform to target important sites in the female genital tract. Physical models will be developed to understand the transport processes and to guide the development of the nanoparticle delivery system.